[CONTRIBUTION FROM
DEPARTMENT OF CHEMISTRY, THE UNIVERSITY OF
THE
NEW MEXICO]
T H E SYNTHESIS OF HEXAHYDROPYRIMIDINES FROM 1,3-DIAMINES AND KETONES OR ALDEHYDES J. L. RIEBSOMER
AND
GLEX H. MOREYI
Received July 18, 1949
I’revious workers (1, 2, 3, 4) have shown that 1,3-diamines will condense with aldehydes or ketones to produce hexahydropyrimidines. We have extended this earlier work by preparing a number of new compounds. Several ketones tried in this study have been found to produce good yields of the corresponding hexahydropyrimidines (I). When benzophenone, ethyl oxomalonate, quinone, and benzalacetone were substituted for the common ketones, none of the expected pyrimidines were obtained. CHz
CH z
A HzC CHz I /
/\
HzC
CHz
RiY
NH
I
1
RN
I
NH
I1
In some instances aldehydes give a comparable reaction (producing compounds of type 11)but for some unknown reason this type of reaction is less general and less satisfactory. Thus when acetaldehyde, butyraldehyde or benzaldehyde was interacted with N-isopropyl-l,3-propanediamine,none of the expected hexahydropyrimidines was isolated. Also, it has been demonstrated that when the aldehyde is formaldehyde biscompounds (111)may form.
2 RNHCHzCHzCHzNHz
xz
H2C
I
RN
+ 3 HCHO
-+
3H20
+
CH2
/\ HzC CHz I I NR \/
CHz
I
N-CHz-N
\/
CH
CHz I11
:It has not been found possible to cause other aldehydes (for example furfural) to behave in a similar manner. Presumably in these reactions the hexahydropyrimidine of type I1 is first formed followed by the interaction of 2 moles of the hexahydropyrimidine and 1 mole of formaldehyde with the loss of 1 mole of water. 1
Present address: Glas-Col Apparatus Co., Inc., Terre Haute, Ind. 245
246
J. L. RIEBSOMER AND GLEN H. MOREY EXPERIMENTAL A.
KETONES AND
1,8-DIAMINES
A number of hexahydropyrimidines were prepared using the same general procedure, which W&B essentially that used by Bergmann, et al. (4). Only one needs t o begiven in detail. Table I summarizes the data. 1-Isopropyl-3-methyl-8-phmylhexahydropyTimidine.A mixture of 34.8 g. (0.3 mole) of N-isopropyl-1 ,a-propanediamine and 36 g. (0.3 mole) of acetophenone was prepared. A little benzene was added and the mixture was heated under conditions t o distill the benzenewater azeotropic mixture through a 4' packed-column. The column was fitted with a decanter stillhead so that the benzene returned constantly t o the reaction mixture. The temperature was gradually increased from 120" to 180" during a 6-hour period, resulting in the removal of 5 g. of water. Upon distillation from a modified Claisen flask a t 20 mm., the product was a colorless liquid which boiled a t 173-175". Yield, 37 g. (57%). Anal. Cdc'd for C&Z&Z: C, 76.96; H , 10.16; N, 12.82; Neut. equiv., 109.12. Found: C, 77.03; H , 10.14; N, 12.80; Neut. equiv., 110.44, B.
ALDEHYDES AND
I,%DIAMINES
Reaction of N-isopropyl-1,S-propanediamine and formaldehyde. In one experiment, a mixture of 58 g. (0.5 mole) of N-isopropyl-l,3-propanediamineand 63 g. (0.75 mole) of 40% aqueous formaldehyde was prepared and heated under the usual conditions t o remove water by distilling the benzene-water azeotropic mixture through a 4' packed-column. By heating for 3 hours from 90 t o 110", a total of 51 g. of water was removed. The residue was distilled and separated into two main fractions. The first fraction, b.p. 74-75' a t 22 mm., analyzed correctly for N-isopropylhexahydropyrimidine;yield 30%. Anal. Calc'd for C T H ~ ~ NN,Z :21.85; Neut. equiv., 64.1. Found: N, 21.41; Neut. equiv., 65.8. The second fraction, b.p. 140-142" a t 3 mm., analyzed correctly for bis-(3-isopropyl1,3-diazacyclohexyl)methane (Type 111) ; yield, 24%. Anal. Calc'd for C16H32N4: N, 20.85; Neut. equiv., 67.06. Found: N, 20.34; Neut. equiv., 70.46. In a second experiment, equimolecular quantities of N-isopropyl-1 ,a-propanediamine and formaldehyde were allowed t o react under the conditions of the preceding experiment. Apparently some of the expected N-isopropylhexahydropyrimidineformed, but it was not sufficiently pure to give a suitable analysis. In a third experiment, 152 g. (1.31 moles) of N-isopropyl-l,3-propanediaminewas dissolved in 100 ml. of methanol. Then 2.8 moles of 40% aqueous formaldehyde was added portionwise while stirring and cooling. The temperature was maintained a t 3040". The mixture was finally heated to 60" on a steam-bath. The methanol and other volatile constituents were removed i n vacuo by heating t o a maximum temperature of 110". The product was distilled a t 2 mm.; yield, 91 g. (70%). Anal. Calc'd for the bis-compound, ClsHasN4:N, 20.85; Molecular weight, 268. Found: N, 21.14; Molecular weight, 264. N-isopropyl-8-lf-fury1)hexahydropyrimidine. A mixture was prepared containing 58 g. (0.5 mole) of N-isopropyl-l,3-propanediamineand 48 g. (0.5 mole) of furfural. Much heat was evolved and the mixture was cooled externally t o prevent the temperature exceeding 50". Benzene was added and the mixture was heated under the usual conditions to remove water. The temperature was increased during a 5-hour period to a maximum of 160°, thus removing 8.5 g:of water. The product whick distilled at 122-123' at 5 mm. weighed 62 g.
(64%). . Anal. Calc'd for CllHI8N20:C, 67.98; H, 9.34; N, 14.42; Neut. equiv., 97.08. Found: C, 67.98; H, 9.53; N, 14.23; Neut. equiv., 91.69. N-(&Hydroxyethyl)hexahydropyrimidine. To 206 g. (1.745 moles) of N-@-hydroxyethyl)-1,3-propanediaminewas added 100 ml. of methanol. To this mixture was added 1.7
THE SYNTHESIS OF HEXAWDROPYRIMIDINES
247
248
J. L. RIEBSOMER AND GLEN H . MOREY
moles of 40% aqueous formaldehyde with stirring and cooling so that the temperature remained a t 45-50'. This mixture was finally heated hour on a steam-bath. The methanol and other volatile constituents were distilled in uacuo up to a pot temperature of 120'. The product which distilled a t 137-140" a t 17 mm. weighed 209 g. (92%). Anal. Calc'd for CsHlJTzO: N, 21.43; Molecular weight, 130.1; Neut. equiv., 65. Found: K, 21.23; Molecular weight, 113; Neut. equiv., 66.5. When furfural was substituted for formaldehyde in the above reaction in an attempt to produce N- (P-hydroxyethyl-2-a-furyl)hexahydropyrimidine, only a black tar was formed. N-(l-ethylhezyl)hesahyd~opyrimidine.To 233 g. (1.28 moles) of K-(2-ethylhexyl)propanediamine was added one mole of aqueous 40% formaldehyde with stirring and cooling so that the temperature was maintained at 45-50'. After the reaction was complete, the more volatile constituents were distilled i n vacuo up to a pot temperature of 130'. The remainder of the product was fractionated a t 10 mm. The main fraction boiled at 120-121" and weighed 194 g. (98%). Anal. Calc'd for C I ~ H ~ BN, N ~14.40; : Molecular weight, 198. Found: N, 14.14; Molecular weight, 214. Bis-3-(S'-di~ul2/Zaminopropyl)-1 ,S-diazac~clohezylmethune.To 243 g. (1.0 mole) of N,N-dibutyl-4-aza-l,7-heptanediamine was added 200 ml. of methanol. T o this mixture was added portionwise 2 moles of aqueous 40% formaldehyde while stirring and cooling t o maintain the temperature a t 40-50". After about 75% of the formaldehyde was added, two layers formed. The mixture was finally heated for a few minutes with steam. The methanol and other volatile constituents were removed in uacuo up to a pot temperature of 130'. Upon distillation, 230 g. (88%) of the expected product was obtained. Anal. Calc'd for CI1HBBN6: N , 16.09; Molecular weight, 522. Found: X, 15.61; Molecular weight, 508. A number of these new hexahydropyridmidines have been tested as insect repellents, but none have been found effective.
+
ACKNOWLEDGIVlENT
The authors are pleased to express their appreciation to the research laboratories of Commercial Solvents Corporation for generous support of this work. SUMMARY
1. Ketones react with 1,3-diamines to give good yields of hexahydropyrimidines. 2. Some aldehydes likewise produce hexahydropyrimidines in good yields, but this type of reaction is less satisfactory. 3. In some instances, when formaldehyde reacts with 1,3-diamines, it has been shown that bis-1 3-diazacyclohexylmethanes may be produced. ALBUQUERQUE, N. M. REFERENCES (1) SCHOLZ, Ber., 32, 2253 (1899). (2) VEER,Rec. trau. chim., 67, 995 (1938). (3) SENKUS,J . Am. Chem. Soc., 08, 1611 (1946). (4) BERGMANN, HERMAN, AND ZIMKIN,J . Org. Chem., 13, 353 (19.28).
